Prostate cancer is the most common noncutaneous malignancy diagnosed in men in the United States. Approximately 27,000 American men will die of metastatic, hormone refractory prostate cancer (MHRCaP) in 2006. Typical life expectancy in the setting of MHRCaP is approximately 18 months, and the only therapy at this point proven to improve survival is docetaxel chemotherapy, with an average improvement in life expectancy by about 2 months. Clearly, more effective therapies in this setting are needed. Proteins that are important in the progression of MHRCaP, including the androgen receptor (AR), Akt and HER2, are client proteins of heat shock protein 90 (HSP90). Preclinically, HSP90 inhibition causes a dose dependent degradation of these client proteins and regression of CaP xenograft tumors. Based on this hypothesis, trials of 17-allylaminogeldanamycin (17-AAG), an HSP90 inhibitor, in CaP have been initiated. Unfortunately, 17-AAG is a problematic compound with formulation difficulties that may interfere with the ability to discern clinical efficacy. Moreover, these ongoing trials are not collecting fresh tumor biopsy material to evaluate the hypothesis that HSP90 inhibition results in degradation of these client proteins. With this grant, we plan to begin a prospective, Phase II clinical trial of a water soluble active metabolite of 17-AAG, IPI-504, in MHRCaP. In this trial we will both determine the clinically efficacy of this compound, using PSA response rate as our primary endpoint, and also examine the hypothesis that HSP90 inhibition results in degradation of the critical client proteins in CaP by performing CT-guided biopsies of tumor metastases both before and during treatment on all subjects. Therefore, we hope to both test the clinical efficacy of IPI-504 in MHRCaP as well as the clinical relevance of the HSP90 hypothesis in CaP. Project relevance. Prostate cancer is the most common noncutaneous malignancy diagnosed in men in the United States and the second leading cause of cancer related death among men. This grant will fund a clinical trial to explore a promising new therapy in metastatic, advanced prostate cancer, which could help delay the progression of this disease. Moreover, this trial incorporates tumor biopsies to better predict patients who will respond to therapy (allowing for less toxicity and more targeted therapy) and understand how this novel therapy affects the tumor cells.